Project Summary/Abstract The prevalence of obesity and type 2 diabetes is greatly influenced by food intake and diet composition. Although multiple studies have explored the complex regulation of food intake, the molecular mechanisms that govern the appetite for specific macronutrients are largely unknown. Recently our laboratory demonstrated that fibroblast growth factor 21 (FGF21) mediates endocrine control of simple sugar intake and sweet taste preference through its actions on the central nervous system. The precise neuronal population that FGF21 targets to mediate its effects, however, remain unidentified. Interestingly, oxytocin neurons have been shown to regulate carbohydrate-specific satiety in a manner similar to that of FGF21. Recent studies have demonstrated that PVN oxytocin neuronal projections and signaling to the mesolimbic dopamine system, or the ?reward center? of the brain, alters dopaminergic activity. Notably, our preliminary data shows that peripheral administration of FGF21 also modulates the mesolimbic dopamine system by increasing dopamine turnover in the nucleus accumbens. We hypothesize that FGF21 regulates simple sugar intake and sweet taste preference through the modulation of the mesolimbic dopamine system, via actions on oxytocin neurons. To test this hypothesis, we will first identify whether FGF21 targets PVN oxytocin neurons by generating a novel mouse model that expresses Tdtomato under the control of the endogenous ?-klotho (obligate FGF21 co- receptor) promoter. Next, we will use complementary mouse models that either knockout or express ?-klotho in oxytocin neurons to determine whether these neurons are required for FGF21-mediated sugar satiety. Finally, we will use optogenetic and chemogenetic stimulation, microdialysis, and targeted pharmacological techniques to determine the mechanism by which FGF21 modulates the mesolimbic dopamine system. In the proposed work, our long-term objective is to identify the central circuit that regulates FGF21-mediated effects on energy homeostasis and reward.